Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, NC, USA.
Comparative Medicine Institute, North Carolina State University, Raleigh, NC, USA.
Nat Biotechnol. 2022 Aug;40(8):1250-1258. doi: 10.1038/s41587-022-01245-x. Epub 2022 Mar 24.
Despite their clinical success, chimeric antigen receptor (CAR)-T cell therapies for B cell malignancies are limited by lengthy, costly and labor-intensive ex vivo manufacturing procedures that might lead to cell products with heterogeneous composition. Here we describe an implantable Multifunctional Alginate Scaffold for T Cell Engineering and Release (MASTER) that streamlines in vivo CAR-T cell manufacturing and reduces processing time to a single day. When seeded with human peripheral blood mononuclear cells and CD19-encoding retroviral particles, MASTER provides the appropriate interface for viral vector-mediated gene transfer and, after subcutaneous implantation, mediates the release of functional CAR-T cells in mice. We further demonstrate that in vivo-generated CAR-T cells enter the bloodstream and control distal tumor growth in a mouse xenograft model of lymphoma, showing greater persistence than conventional CAR-T cells. MASTER promises to transform CAR-T cell therapy by fast-tracking manufacture and potentially reducing the complexity and resources needed for provision of this type of therapy.
尽管嵌合抗原受体 (CAR)-T 细胞疗法在治疗 B 细胞恶性肿瘤方面取得了临床成功，但由于其体外制造过程漫长、昂贵且劳动强度大，可能导致细胞产品组成不均一。在这里，我们描述了一种可植入的多功能藻酸盐支架用于 T 细胞工程和释放 (MASTER)，它简化了体内 CAR-T 细胞的制造过程，并将处理时间缩短到了一天。当用人类外周血单核细胞和编码 CD19 的逆转录病毒颗粒接种时，MASTER 为病毒载体介导的基因转移提供了适当的界面，并且在皮下植入后，介导功能性 CAR-T 细胞在小鼠中的释放。我们进一步证明，体内生成的 CAR-T 细胞进入血液，并在淋巴瘤的小鼠异种移植模型中控制远端肿瘤生长，其持久性优于传统的 CAR-T 细胞。MASTER 有望通过快速制造来改变 CAR-T 细胞疗法，并可能减少提供这种类型治疗所需的复杂性和资源。
